tbuckley/cabot-search huggingface dataset:
Abstract 2217: Novel risk stratification utilizing NanoString for HPV+ head and neck cancer patients
Authors: Sulgi Kim, Travis Schrank, Aditi Kothari, Hina Rehmani, Jason Tasoulas, Xue Li, Wendell Yarbrough, Natalia Isaeva
Journal: Cancer Research (2023)

Abstract Incidence of human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) has dramatically increased in the U.S. surpassing cervical cancer since 2012. Among HNSCC, HPV+ HNSCC patients have a favorable prognosis; however, approximately 20-30% suffer recurrence. Given the morbidity of current therapy, therapeutic de-escalation for HPV+ HNSCC is being explored in many clinical trials but is hampered by absence of accurate molecular classifiers to identify tumors at high and low risk of recurrence. Being able to risk stratify patients can help with therapeutic decisions, maintain high cure rates and decrease treatment associated complications. We assemble a NanoString panel to capture our recently developed NF-κB RNA signature that can distinguish patients requiring aggressive therapy from patients who are appropriate for reduced intensity treatment. Our custom gene set can select HPV+ head and neck cancer patients that may benefit from therapy de-escalation. Several advantages of using a NanoString technology, including smaller amounts of patient samples and less processing time that allow real-time patient-specific results. This makes our Nanostring panel suitable to be used in clinic to identify HPV+ head and neck cancer patients for therapeutic de-escalation without compromising their survival. Citation Format: Sulgi Kim, Travis Schrank, Aditi Kothari, Hina Rehmani, Jason Tasoulas, Xue Li, Wendell Yarbrough, Natalia Isaeva. Novel risk stratification utilizing NanoString for HPV+ head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2217.
Abstract 5021: Preclinical evaluation of immunomodulatory effects of aurora kinase inhibition in HPV+ cancers
Authors: Pragya Sinha, Soma Ghosh, Faye M. Johnson, Jagannadha K. Sastry
Journal: Cancer Research (2023)

Abstract Human papillomavirus (HPV) is the causative agent of cervical cancer and some cancers of the penis, vulva, vagina, anus, and oropharynx. In an earlier study, we identified Aurora Kinase (AK) inhibitors from a large-scale drug screening as a unique class of reagents to induce selective apoptosis in HPV+ human tumor cells in vitro and in vivo (using HPV+ PDX mouse models). We tested the in vivo efficacy of alisertib, an Aurora Kinase A inhibitor, in an immunocompetent mouse model (mEER) for HPV+ oropharyngeal cancers. In preparation for this, we first tested 300 nM alisertib on 3 HPV+ murine cancer cell lines: TC-1, C3.43, and mEER for 48h. We observed that when compared to the vehicle (DMSO) control group, the level of phospho Aurora Kinase A was completely inhibited. Furthermore, in multiple HPV+ murine tumor cell lines we observed significant apoptosis as measured by annexin V 7-AAD staining along with higher cell surface expression of calreticulin (CRT), and high mobility group box 1 protein (HMGB1) which are markers for immunogenic cell death (ICD). Both CRT and HMGB1 serve as “eat me” signals that in turn trigger APC-mediated dead-cell antigen uptake, a crucial event for priming the responses from the innate immune system. In support of this, we observed that in a co-culture setting, the conditioned medium from alisertib-treated tumor cells increased the frequencies of CD8+ cells expressing GnzB as well as a significant decrease in the population of T regulatory cells (Tregs) (CD4+ FoxP3+). Additionally, we observed an increase in the innate immune natural killer cell subset. Future studies will explore the in vivo efficacy of Aurora Kinase inhibition along with immune checkpoint blockade and/or therapeutic vaccination. Our proposed research will have a positive impact because we will gain insight into the immune responses underlying the co-dependency of HPV+ cancers on Aurora kinase. Our research may lead to an increase in the rates of long-term, durable clinical responses or may allow for therapy de-escalation. Citation Format: Pragya Sinha, Soma Ghosh, Faye M. Johnson, Jagannadha K. Sastry. Preclinical evaluation of immunomodulatory effects of aurora kinase inhibition in HPV+ cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5021.
Abstract 5520: Research Ready graphic-style story to support future research participation among adolescents
Authors: Lauren Bates, Susan Gertz, Susan Hershberger, Melinda Butsch Kovacic
Journal: Cancer Research (2023)

Abstract Historically, marginalized adults are more likely to be mistrustful of health research worrying both about its invasiveness and their own safety. As a result, many decline to participate. Adolescents have a much lower perception of risk compared to adults and are also susceptible to peer pressure and socialized trust or mistrust from their parents and family members, which can influence risk perception. As encouraging equitable participation in research becomes an important tool in the fight against cancer disparities, We Engage 4 Health created a graphic-style story “Research Ready” to help community members learn the 3 P’s: the purpose of cancer research, how they are kept safe while participating, and why people from diverse backgrounds are needed to participate. An accompanying Research Review Activity was also included to further support participants’ decision-making regarding research participation. Two groups of diverse adolescents were asked to read the story aloud together in small groups and then discuss an active research study targeting adolescents using the review activity with a scientist to consider whether the first the teen story character (Vito) and ultimately themselves, should consider participation in the study and to identify what information was needed from study staff to better be able to make a decision based on their values and accurate information provided by study staff. Group 1 included 45 adolescents that were 68% African American and 10% European American. Group 2 included 73 high schoolers that were 78% Asian, 15% European American, and 5% African American. Post-discussion surveys indicated that only 9% and 3% in group 1 and group 2 respectively had previously participated in health research. However, after the story discussion, 83% and 89% indicated they thought it would be safe to participate in research and 76% and 89% indicated a willingness to participate in research in the future. Finally, 60% collectively enjoyed the story’s graphic-style format. These data suggest Research Ready to be potentially useful in promoting future research participation and may be especially useful in engaging ethnic/racial groups commonly underrepresented in cancer research. Citation Format: Lauren Bates, Susan Gertz, Susan Hershberger, Melinda Butsch Kovacic, We Engage 4 Health Community-Academic Partnership. Research Ready graphic-style story to support future research participation among adolescents. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5520.
Abstract 5363: MicroArray-based MethylationToActivity: Advancing biological knowledges from DNA methylation profiles of patient tumors
Authors: Karissa Dieseldorff Jones, Waise Quarni, Daniel Putnam, Shivendra Singh, Qiong Wu, Jun Yang, Xiang Chen
Journal: Cancer Research (2023)

Abstract DNA methylation (DNAm) is a relatively stable regulatory epigenetic mechanism. Although accurate DNAm classifiers have been built for early detection of cancer and subtype classifications, its transcriptional regulatory roles remain unclear. To address this challenge, we developed a deep-learning framework MethylationToActivity (M2A) that accurately predicts individual promoter activity from WGBS methylomes. As array-based methylome is the most common epigenetic data from patients’ tumor samples, we redesigned M2A’s raw features and model topology for array methylomes, which shows an accurate prediction of the promoter activity (R2 = 0.74), approaching its WGBS counterpart (R2 = 0.79). Transfer learning improves the prediction accuracy to 0.77. In a primary rhabdomyosarcoma cohort, M2A prioritized candidate genes with strong subtype-specific alternative promoter usage (APU) and identified distinct isoforms of a subgroup of APU genes including NAV2 expressed in the two major subtypes (aRMS and eRMS). Molecular experiments revealed that PAX3-FOXO1 directly binds to the aRMS-specific promoter and is required for its active transcription. Genetic deletion of PAX3-FOXO1 leads to NAV2 APU. Overexpression of aRMS-specific NAV2 isoform significantly promoted cell proliferation, supporting its oncogenic function. These data indicate that PAX3-FOX1 is critical for APU in aRMS. We conclude that the new M2A provides vast insight into downstream functional interpretation of differential DNAm patterns. Citation Format: Karissa Dieseldorff Jones, Waise Quarni, Daniel Putnam, Shivendra Singh, Qiong Wu, Jun Yang, Xiang Chen. MicroArray-based MethylationToActivity: Advancing biological knowledges from DNA methylation profiles of patient tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5363.
Abstract 6360: <i>In vivo</i> antitumor efficacy evaluation of ASC63, an oral small molecule PD-L1 inhibitor, in a humanized mouse tumor model
Authors: Jinzi J. Wu, Handan He
Journal: Cancer Research (2023)

Abstract Background: ASC63 is an oral small molecule programmed cell death-ligand 1 (PD-L1) inhibitor. After oral dosing, ASC63 is rapidly absorbed and converted to its pharmacologically active metabolite ASC63-A in vivo. In vitro studies showed that ASC63-A could activate PD-L1 dimerization and internalization from cell membrane, thus interfere PD-1/PD-L1 interaction and enhance T-cell activation. Here we report the in vivo antitumor efficacy of ASC63 in a humanized mouse tumor model. Methods: 0.5×106 human PD-L1 knock in CT26 cells (CT26-hPD−L1) were implanted subcutaneously into BALB/c mice for tumor development. When the average tumor volume reached approximately 100 mm3, mice were randomly assigned (post-grouping, PG) and treated with vehicle, reference drug (10 mg/kg Atezolizumab intravenous injection twice a week [BIW]), 50 or 100 mg/kg ASC63 oral dosing twice a day (BID) for 18 days. Body weights and tumor volumes were measured regularly, and tumor growth inhibitions (TGI) of different groups were compared. TGI was calculated using the formula: TGI (%) =[1-(TRTV-1)/(CRTV-1)] ×100, where TRTV= mean relative tumor volume (RTV) of treatment group; CRTV= mean of control group. Results: At PG-D18, the tumor volume of vehicle group reached 1548 mm3, and Atezolizumab, 50 and 100 mg/kg AS63 groups showed TGI values of 35.17, 17.12 and 36.87%, respectively. Atezolizumab 10 mg/kg BIW and ASC63 100 mg/kg BID produced similar antitumor activities. One mouse in 100 mg/kg ASC63 group had body weight loss more than 10% at PG-D6, and was back to normal at PG-D9 after extra nutrition was provided, while the rest of mice showed a gradually increase in body weight during the study. No significant difference of body weight or body weight change was found among different groups of mice. Conclusion: Results of this study show that ASC63 is in general well tolerated in CT26-hPD−L1 humanized mouse tumor model, and ASC63 has comparable antitumor efficacy as the FDA-approved PD-L1 antibody, Atezolizumab. ASC63 is an oral small molecule PD-L1 inhibitor, and thus will have better patient compliance than injective PD-1/PD-L1 antibody. Results of this study support the continued investigation of ASC63. Citation Format: Jinzi J. Wu, Handan He. In vivo antitumor efficacy evaluation of ASC63, an oral small molecule PD-L1 inhibitor, in a humanized mouse tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6360.
Abstract 663: Resistin mediates the immunoediting activity exerted by primary human macrophages towards mesothelioma cells
Authors: Malik Hamaidia, Majeed Jamakhani, Jean-Rock Jacques, Alexis Fontaine, Arnaud Scherpereel, Eric Wasielewski, Louis Renaud, Vincent Heinen, Bernard Duysinx, Luc Willems
Journal: Cancer Research (2023)

Abstract Tumor-associated macrophages (TAM) are particularly abundant (i.e. 27% ± 9%) in the microenvironment of malignant pleural mesothelioma (MPM). These macrophages do not correspond to classical (M1) and alternatively-activated (M2) phenotypes but, instead, are shaped by local inflammatory mediators released in the pleura. We previously showed that, besides classical functions exerted by macrophages (i.e. phagocytosis, cytokine expression and antigen presentation), murine RAW264.7 cells are directly cytotoxic to MPM tumors (Hamaidia et al, JCI Insight 4:e128474). Upon direct cell-to-cell contact, RAW264.7 macrophages kill mesothelioma cells by a mechanism of oxeiptosis involving the enhancer of zeste homolog 2 (EZH2) methyltransferase. We have now investigated this immune-editing activity in human mesothelioma. We show that M1-activated primary macrophages are more cytotoxic for M14K cells than M2. The killing activity of M1 macrophages is dependent on NADPH oxidase activity and peroxynitrite levels. Mesothelioma cells and M2 macrophages interact through an inhibitory synapse characterized by engagement of the PD-1 receptor. Consistently, the immune-editing activity of M2 macrophages is partially restored in presence of neutralizing anti-PD1 antibody. Primary human macrophages cultured in presence of pleural effusions of MPM patients are less cytotoxic than M1 and are unable to inhibit tumor growth in mice. Macrophages differentiated in pleural effusions display a broad spectrum of cytotoxic activities (i.e. from complete inactivity to rates similar to those of M2). Luminex profiling of pleural fluids has identified a series of key mediators associated with the cytotoxic phenotype. The best correlation is obtained with resistin (RETN, FIZZ3, ADSF). Recombinant human resistin improves the killing activity of pleural effusion macrophages in cell culture. Gene transduction of RETN in RAW264.7 impairs growth of AB12 tumors in BALB/c mice. In conclusion, we have shown that resistin is the main factor that mediates immunoediting activity exerted by primary human macrophages towards mesothelioma cells, opening new prospects for therapeutic intervention. Citation Format: Malik Hamaidia, Majeed Jamakhani, Jean-Rock Jacques, Alexis Fontaine, Arnaud Scherpereel, Eric Wasielewski, Louis Renaud, Vincent Heinen, Bernard Duysinx, Luc Willems. Resistin mediates the immunoediting activity exerted by primary human macrophages towards mesothelioma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 663.
Abstract 6353: Combination of poly-γ-glutamic acid with anti PD-L1 blockade leads to improved anti-tumor activity in murine models
Authors: Jae-Pyung Jang, Jae Chul Choi, Kyung-Soo Hahm, Do Young Lee, Young-Chul Park
Journal: Cancer Research (2023)

Abstract Immune checkpoint inhibitors(ICIs) have been shown to be key role in cancer therapy. Especially, antibodies targeting programmed cell death ligand1(PD-L1) promoted T cells to activate immune response against cancer cells. However, the current ICIs still have insignificant to motivate effective antitumor immunity by blocking PD-1/PD-L1 pathway and the regulatory network of PD-L1 by cytokines in the tumor microenvironment remains to be uncovered. Previously, we have reported the anti-cancer effects of combination treatment with a natural product, poly-γ-glutamic acid(γ-PGA), and PD-1 blockade. Now, we showed that combination therapy with anti PD-L1 and γ-PGA overcome the limits of ICIs and enhance anticancer effect in murine melanoma(B16F10). In vivo efficacy studies were performed by intraperitoneal injection of antibody targeting PD-L1 and oral administration of γ-PGA in C57BL/6 model transplanted with B16F10 melanoma cell. Systemic changes in immunophenotype were measured by tumor volume size and survival rate. The splenocytes were isolated from mice and the populations of myeloid-driven suppressor cells(MDSCs) and CD4/CD8 T cells were analyzed by FACS. Combination therapy with γ-PGA and anti PD-L1 blockade showed dramatically more suppressive tumor growth and enhanced long-term survival rate than other monotherapic treatment. In addition, γ-PGA was shown to play a role in the immune modulation of tumor microenvironment by activation of T cells and inhibition of MDSCs so as to prevent tumors from immune escape. Therefore, we suggest that γ-PGA can promote ICI-mediated antitumor responses by the transformation of "cold tumors" into “hot tumors” Citation Format: Jae-Pyung Jang, Jae Chul Choi, Kyung-Soo Hahm, Do Young Lee, Young-Chul Park. Combination of poly-γ-glutamic acid with anti PD-L1 blockade leads to improved anti-tumor activity in murine models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6353.
Abstract 4130: Genetically modified hematopoietic stem cells for improvement of immunotherapies against solid malignancies
Authors: Laura Falceto Font, Dan Jin, Connor P. Francis, Bayli DiVita Dean, John W. Figg, Brianna McDonald, Catherine Flores
Journal: Cancer Research (2023)

Abstract Hematopoietic stem cells (HSCs) are routinely used in the clinic to treat several diseases and their side effects, including cancers. Our group has previously shown that the combination of HSCs with two different immunotherapies improves survival in brain tumors, but it is still not curative. In this study, we wanted to explore whether modifying HSCs can drive them into a dendritic cell phenotype or suppress them from becoming immunosuppressive myeloid cells at the tumor microenvironment to increase survival when combined with immunotherapy in a glioma model. HSCs have been historically challenging to grow in vitro for long-term culture due to the short periods of time they remain undifferentiated, which creates an extra challenge for the genetic modification of HSCs. Here, we test different in vitro conditions for expansion and modification of murine and human HSCs by employing the following methods for modulation of HSCs: shRNA lentiviral delivery, overexpression constructs, RNA electroporation, CRISPR, and AAV. This study describes the efficacy of each method as well as the observed limitations of each technique on HSCs. Furthermore, preliminary data shows IL6R downregulation as a candidate for driving HSCs into the dendritic cell lineage. Ultimately, these genetically modified cells will be used as an adjuvant therapy to improve the efficacy of various immunotherapeutic strategies against solid malignancies. Citation Format: Laura Falceto Font, Dan Jin, Connor P. Francis, Bayli DiVita Dean, John W. Figg, Brianna McDonald, Catherine Flores. Genetically modified hematopoietic stem cells for improvement of immunotherapies against solid malignancies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4130.
Abstract 632: Exploiting pyroptosis in melanoma brain metastasis
Authors: Maria R. Cavallo
Journal: Cancer Research (2023)

Abstract Melanoma is the deadliest form of skin cancer due to its frequent metastasis to the brain. Melanoma brain metastases (MBM) are a significant clinical challenge, and current model systems and therapeutic strategies are poor. Inhibitors targeting the most common oncogenic driver of melanoma, BRAFV600E (BRAFi), disrupt mitogenic signaling and promote caspase-3 associated cell death. Though caspase-3 is a well-known apoptotic driver, it can also cleave Gasdermin E (GSDME) to create pore-forming N-terminal fragments that oligomerize at plasma and mitochondrial membranes and trigger pyroptosis - a form of immunogenic cell death (ICD). Our recent work illustrates the importance of GSDME mediated pyroptosis and associated immunogenicity in providing a durable therapeutic response against melanoma. Since pyroptosis can be activated by GSDME cleavage via caspase-3, and is prominent in various neuropathologies, a better understanding of the interplay between central nervous system (CNS) immune cells and BRAFi-mediated ICD is critical for designing more effective therapies against MBM. Here, we engineered a panel of inducible pyroptotic melanoma cells to model BRAFi-mediated pyroptosis. Using ex vivo CNS slice co-cultures, we found that inducible N-GSDME expression in human and murine melanoma cells drives propidium iodide uptake and release of inflammatory activators like HMGB1 and IL-1 - hallmarks of pyroptosis. Importantly, conditioned media from these pyroptotic cells stimulates a more robust phagocytic response from resident macrophages of the CNS and pyroptotic melanoma elicit stronger cytotoxicity from syngeneic CD8+ T cells, further highlighting the benefits of BRAFi-mediated ICD. Our findings provide evidence that resident CNS immune cells and peripheral T cells respond to pyroptotic melanoma, suggesting that induction of ICD should be a consideration in the development of anti-MBM therapies. Citation Format: Maria R. Cavallo. Exploiting pyroptosis in melanoma brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 632.